title: Connexin defects underlie arrhythmogenic right ventricular cardiomyopathy in a novel mouse model.
abstract: Arrhythmogenic right ventricular cardiomyopathy (ARVC) termed a 'disease of the desmosome' is an inherited cardiomyopathy that recently underwent reclassification owing to the identification of left-dominant and biventricular disease forms. Homozygous loss-of-function mutations in the desmosomal component, desmoplakin, are found in patients exhibiting a biventricular form of ARVC; however, no models recapitulate the postnatal hallmarks of the disease as seen in these patients. To gain insights into the homozygous loss-of-function effects of desmoplakin in the heart, we generated cardiomyocyte-specific desmoplakin-deficient mice (DSP-cKO) using ventricular myosin light chain-2-Cre mice. Homozygous DSP-cKO mice are viable but display early ultrastructural defects in desmosomal integrity leading to a cardiomyopathy reminiscent of a biventricular form of ARVC, which includes cell death and fibro-fatty replacement within the ventricle leading to biventricular dysfunction, failure and premature death. DSP-cKO mice also exhibited ventricular arrhythmias that are exacerbated with exercise and catecholamine stimulation. Furthermore, DSP-cKO hearts exhibited right ventricular conduction defects associated with loss of connexin 40 expression and electrical wavefront propagation defects associated with loss of connexin 43 expression. Dose-dependent assessment of the effects of loss of desmoplakin in neonatal ventricular cardiomyocytes revealed primary loss of connexin 43 levels, phosphorylation and function independent of the molecular dissociation of the mechanical junction complex and fibro-fatty manifestation associated with ARVC, suggesting a role for desmoplakin as a primary stabilizer of connexin integrity. In summary, we provide evidence for a novel mouse model, which is reminiscent of the postnatal onset of ARVC while highlighting mechanisms underlying a biventricular form of human ARVC.
authors.affiliation: Department of Medicine.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Lyon
authors.forename: Valeria
authors.initials: V
authors.lastname: Mezzano
authors.forename: Adam T
authors.initials: AT
authors.lastname: Wright
authors.forename: Emily
authors.initials: E
authors.lastname: Pfeiffer
authors.forename: Joyce
authors.initials: J
authors.lastname: Chuang
authors.forename: Katherine
authors.initials: K
authors.lastname: Banares
authors.forename: Allan
authors.initials: A
authors.lastname: Castaneda
authors.forename: Kunfu
authors.initials: K
authors.lastname: Ouyang
authors.forename: Li
authors.initials: L
authors.lastname: Cui
authors.forename: Riccardo
authors.initials: R
authors.lastname: Contu
authors.forename: Yusu
authors.initials: Y
authors.lastname: Gu
authors.forename: Sylvia M
authors.initials: SM
authors.lastname: Evans
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Omens
authors.forename: Kirk L
authors.initials: KL
authors.lastname: Peterson
authors.forename: Andrew D
authors.initials: AD
authors.lastname: McCulloch
authors.forename: Farah
authors.initials: F
authors.lastname: Sheikh
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001145:Arrhythmias, Cardiac / Q000235:genetics; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D053840:Brugada Syndrome; D000075224:Cardiac Conduction System Disease; D002395:Catecholamines / Q000494:pharmacology; D018031:Connexin 43 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D017630:Connexins / Q000172:deficiency* / Q000235:genetics; D051180:Desmoplakins / Q000172:deficiency; D004195:Disease Models, Animal; D004562:Electrocardiography; D015870:Gene Expression; D006321:Heart / Q000187:drug effects; D006329:Heart Conduction System / Q000002:abnormalities; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D010766:Phosphorylation; D010805:Physical Conditioning, Animal / Q000009:adverse effects; D000097003:Gap Junction alpha-5 Protein
chemical_list: D002395:Catecholamines; D018031:Connexin 43; D017630:Connexins; D051180:Desmoplakins; D000097003:Gap Junction alpha-5 Protein